Apoptotic caspases are thought to play critical roles in elimination of excessive and non-functional synapses and removal of extra cells during early developmental stages. Hence, an impairment of ...this process may thus constitute a basis for numerous neurological and psychiatric diseases. This view is especially relevant for dopamine due to its pleiotropic roles in motor control, motivation and reward processing. Here, we have analysed the effect of caspase-3 depletion on the development of catecholaminergic neurons and performed a wide array of neurochemical, ultrastructural and behavioural assays. To achieve this, we performed selective deletion of the Casp3 gene in tyrosine hydroxylase (TH)-expressing cells using Cre-loxP-mediated recombination. Histological evaluation of most relevant catecholaminergic nuclei revealed the ventral mesencephalon as the most affected region. Stereological analysis demonstrated an increase in the number of TH-positive neurons in both the substantia nigra and ventral tegmental area along with enlarged volume of the ventral midbrain. Analysis of main innervating tissues revealed a rather contrasting profile. In striatum, basal extracellular levels and potassium-evoked DA release were significantly reduced in mice lacking Casp3, a clear indication of dopaminergic hypofunction in dopaminergic innervating tissues. This view was sustained by analysis of TH-labelled dopaminergic terminals by confocal and electron microscopy. Remarkably, at a behavioural level, Casp3-deficient mice exhibited impaired social interaction, restrictive interests and repetitive stereotypies, which are considered the core symptoms of autism spectrum disorder (ASD). Our study revitalizes the potential involvement of dopaminergic transmission in ASD and provides an excellent model to get further insights in ASD pathogenesis.
•Casp3 gene deletion within TH+ neurons impairs midbrain development.•CASP3 has a key role in shaping the synaptic midbrain connections.•TH-CASP3KO mice display core symptoms of ASD.•TH-CASP3KO mice exhibit dopaminergic hypofunction.•Our study sustains the importance of DA-associated pathways in the aetiology of ASD.
Oxidative stress is a major signature of spinal cord injury (SCI). The altered levels of various oxidative stress markers have been demonstrated in acute and chronic SCI. However, the variation of ...these markers in patients with chronic SCI depending on the time since the initial injury has not been explored yet.
Our aim was to measure plasma levels of malondialdehyde (MDA), a marker of lipid peroxidation in patients with SCI stratified in different periods of suffering the injury (0-5 years, 5-10 years, and more than 10 years).
This cross-sectional study enrolled patients with SCI (N = 105) from different periods of the lesion and healthy control (HC) subjects (N = 38): short period (SCI SP, N = 31, time of evolution less than 5 years); early chronic (SCI ECP, N = 32, time of evolution 5-15 years); and late chronic (SCI LCP, N = 42, time of evolution more than 15 years). The plasma levels of MDA were measured using a commercially available colorimetric assay.
Patients with SCI had significantly higher plasma levels of MDA than HC subjects. Receiver operating characteristic (ROC) curve analysis for plasma MDA levels in patients with SCI demonstrated areas under the curve (AUC) of 1 (HC vs. SCI-SP); 0.998 (HC vs. SCI-ECP); and 0.964 (HC vs. SCI-LCP). Additionally, three ROC curves were used to compare the different concentrations of MDA between the subgroups of patients with SCI, and the resulting AUCs were: 0.896 (SCI-SP vs. SCI-ECP); 0.840 (SCI-ECP vs. SCI-LCP); and 0.979 (SCI-SP vs. SCI-LCP).
Plasma concentration of MDA can be considered as an oxidative stress biomarker to assess the prognosis of SCI in chronic stages.
Abstract Background Diet is a key modifiable risk for many chronic diseases, but it remains unclear whether dietary patterns from one study sample are generalizable to other independent populations. ...Objective The primary objective of this study was to assess whether data-driven dietary patterns from one study sample are applicable to other populations. The secondary objective was to assess the validity of two criteria of pattern similarity. Methods Six dietary patterns—Western (n=3), Mediterranean, Prudent, and Healthy— from three published studies on breast cancer were reconstructed in a case-control study of 973 breast cancer patients and 973 controls. Three more internal patterns (Western, Prudent, and Mediterranean) were derived from this case-control study’s own data. Statistical analysis Applicability was assessed by comparing the six reconstructed patterns with the three internal dietary patterns, using the congruence coefficient (CC) between pattern loadings. In cases where any pair met either of two commonly used criteria for declaring patterns similar (CC ≥0.85 or a statistically significant P <0.05 Pearson correlation), then the true similarity of those two dietary patterns was double-checked by comparing their associations to risk for breast cancer, to assess whether those two criteria of similarity are actually reliable. Results Five of the six reconstructed dietary patterns showed high congruence (CC >0.9) to their corresponding dietary pattern derived from the case-control study’s data. Similar associations with risk for breast cancer were found in all pairs of dietary patterns that had high CC but not in all pairs of dietary patterns with statistically significant correlations. Conclusions Similar dietary patterns can be found in independent samples. The P value of a correlation coefficient is less reliable than the CC as a criterion for declaring two dietary patterns similar. This study shows that diet scores based on a particular study are generalizable to other populations.
Spinal cord injury (SCI) is a progressive and complex neurological disorder accompanied by multiple systemic challenges. Peripheral immune dysfunction is a major event occurring after SCI, especially ...in its chronic phase. Previous works have demonstrated significant changes in different circulating immune compartments, including in T cells. However, the precise characterization of these cells remains to be fully unraveled, particularly when considering important variants such as the time since the initial injury. In the present work, we aimed to study the level of circulating regulatory T cells (Tregs) in SCI patients depending on the duration of evolution. For this purpose, we studied and characterized peripheral Tregs from 105 patients with chronic SCI using flow cytometry, with patients classified into three major groups depending on the time since initial injury: short period chronic (SCI-SP, <5 years since initial injury); early chronic (SCI-ECP, from 5-15 years post-injury) and late chronic SCI (SCI-LCP, more than 15 years post-injury. Our results show that both the SCI-ECP and SCI-LCP groups appeared to present increased proportions of CD4+ CD25+/low Foxp3+ Tregs in comparison to healthy subjects, whereas a decreased number of these cells expressing CCR5 was observed in SCI-SP, SCI-ECP, and SCI-LCP patients. Furthermore, an increased number of CD4+ CD25+/high/low Foxp3 with negative expression of CD45RA and CCR7 was observed in SCI-LCP patients when compared to the SCI-ECP group. Taken together, these results deepen our understanding of the immune dysfunction reported in chronic SCI patients and how the time since initial injury may drive this dysregulation.
Schools are in a position to connect children and adolescents suspected of being victims of violence with an external source of support by making referrals to external agencies. However, several ...studies have identified obstacles that hinder early reporting among school staff members. Very few studies have applied a mixed-method approach to try to understand this sensitive issue. The current study used this approach to analyze to what extent the students suspected of being victimized match the ones reported by active school staff members in Spain (n = 453, 83.5% females, age: M = 42.23, SD = 9.46). We classified the reasons given for not reporting the potential victimization cases encountered and made comparisons to determine whether there were differences in the level of knowledge, or in the sociodemographic characteristics, of respondents who gave different reasons for not reporting. Although 73.5% of school staff members had detected at least one potential case, 40.8% of them referred it to an external agency. The most common reasons for lack of reporting included deciding not to do so once concerns had been shared within the school and believing that one must be certain or that only serious violence should be reported. The findings of this study may help to further understand the decisions not to report certain suspicions of potential victimization cases to external agencies by school staff. There is an urgent need to raise awareness about the duty to report these concerns to external agencies, even in the absence of agreement from the school management team. Members of school staff need to be strongly encouraged to become familiar with the existing protocols.
Lysophosphatidic acid (LPA) affects several female reproductive functions through G-protein-coupled receptors. LPA contributes to embryo implantation via the lysophospholipid LPA
receptor. In the ...present study we investigated the participation of endogenous LPA signalling through the LPA
receptor in vascularisation and decidualisation, two crucial events at the maternal-fetal interface. Pregnant rats were treated with diacylglycerol pyrophosphate (DGPP), a highly selective antagonist of LPA
receptors, on Day 5 of gestation. Pregnant rats received intrauterine (i.u.) injections of single doses of DGPP (0.1mgkg
) in a total volume of 2μL in the left horn (treated horn) in the morning of GD5. DGPP treatment produced aberrant embryo spacing and increased embryo resorption. The LPA
receptor antagonist decreased the cross-sectional length of the uterine and arcuate arteries and induced histological anomalies in the decidua and placentas. Marked haemorrhagic processes, infiltration of immune cells and tissue disorganisation were observed in decidual and placental tissues from sites of resorption. The mRNA expression of three vascularisation markers, namely interleukin 10 (Il10), vascular endothelial growth factor (Vegfa) and vascular endothelial growth factor receptor 1 (Vegfr1), was reduced at sites of resorption from Day 8. The results show that the disruption of endogenous LPA signalling by blocking the LPA
receptor modified the development of uterine vessels with consequences in the formation of the decidua and placenta and in the growth of embryos.
Spinal cord injury (SCI) is a devastating and disabling medical condition generally caused by a traumatic event (primary injury). This initial trauma is accompanied by a set of biological mechanisms ...directed to ameliorate neural damage but also exacerbate initial damage (secondary injury). The alterations that occur in the spinal cord have not only local but also systemic consequences and virtually all organs and tissues of the body incur important changes after SCI, explaining the progression and detrimental consequences related to this condition. Psychoneuroimmunoendocrinology (PNIE) is a growing area of research aiming to integrate and explore the interactions among the different systems that compose the human organism, considering the mind and the body as a whole. The initial traumatic event and the consequent neurological disruption trigger immune, endocrine, and multisystem dysfunction, which in turn affect the patient's psyche and well-being. In the present review, we will explore the most important local and systemic consequences of SCI from a PNIE perspective, defining the changes occurring in each system and how all these mechanisms are interconnected. Finally, potential clinical approaches derived from this knowledge will also be collectively presented with the aim to develop integrative therapies to maximize the clinical management of these patients.
•Development of plasma and wet chemical treatment of polyimide for CVD-grown graphene transfer processes.•Development of a multi-transfer process to reduce resistivity.•Low sheet resistance (800Ω/sq) ...obtained by the combination of HCl treatment and four transfer iterations.
This work explores the use of polyimide substrates for the development of flexible graphene-based devices. Single layer graphene was synthesized by chemical vapour deposition and transferred to untreated and treated polyimide substrates. Of the four different surface treatments, the tetrafluoromethane/oxygen plasma and, especially, hydrochloric acid bath treatments showed the best performance, as they reduced the resistivity of the graphene samples by as much as 46%. At the same time, resistivity was also reduced by as much as 96% due to the increase in the graphene coverage area as a result of repeating the transfer process up to four times. The combination of HCl treatment and transfer iteration led to the samples acquiring a sheet resistance of 800Ω/sq. To the best of our knowledge, this is the lowest value ever reported in the literature for graphene samples on conventional flexible polymeric substrates and, in particular, in polyimide, the most widely used material for flexible applications. This result represents a major contribution to the development of graphene-based flexible devices.
The superoxide dismutase (SOD) is the principal antioxidant defense system in the body that is activated by a reactive oxygen species. Some variants of the SOD2 gene have been associated with cancer. ...The rs4880 variant was determined by PCR real-time and the rs5746136 variant by PCR-RFLP in healthy subjects and in breast cancer (BC) patients. The rs4880 and rs5746136 variants were associated with BC susceptibility when BC patients and the control group were compared for the CT, TT, CTCC, and the T alleles (p < 0.05). The CT genotype of the rs4880 variant showed significant statistical differences in patients and controls aged ≤ 45 years old, and with hormonal consumption (p < 0.05). The rs4880 variant was associated with BC patients with CTTT genotype and obesity, the presence of DM2-SAH, and a non-chemotherapy response (p < 0.05). Additionally, the rs5746136 variant was associated with susceptibility to BC with Ki-67 (≥20%), luminal A type BC, and a chemotherapy partial response (p < 0.05) in BC patients who carry TT, TC, and CTTT genotypes, respectively. The haplotype T/T (OR 1.98; 95% CI 1.20−3.26, p = 0.005) was observed to be a risk factor for BC. The rs4880 and rs5746136 variants in the SOD2 gene were associated with BC susceptibility.
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